Science

Platforms that
Accelerate Drug Discovery

Overview

Arrowhead has established a robust and versatile drug discovery and development platform based on proprietary technologies, broad licenses to fundamental intellectual property and extensive scientific expertise after more than a decade working on RNAi-based therapies. This platform enables the company to develop effective new therapies rapidly, cost effectively and potentially with lower risk relative to traditional approaches.

RNA Interference

One of the most important recent advances in biology, the discovery of RNA interference, or RNAi, led to a Nobel Prize in 2006. RNAi refers to a natural cellular mechanism whereby short oligonucleotide molecules called RNAi triggers silence gene expression and regulate the production of proteins. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing to target and shut down specific genes that cause disease. This mechanism offers many potential advantages in the development of disease therapies, including the ability to target a broad range of genes and proteins with high specificity, and also target disease pathways that have proven difficult to address with traditional small molecule and biologic therapeutics.

This figure depicts the mechanism by which gene silencing occurs. Double stranded RNAi triggers are introduced into a cell and get loaded into the RNA-induced silencing complex, or RISC. The strands are separated leaving an active RISC/RNAi trigger complex. This complex can then pair with and degrade the complementary messenger RNAs, or mRNA, and stop the production of the target proteins. RNAi is a catalytic process, so each RNAi trigger can degrade mRNA hundreds of times, which results in a relatively long duration of effect for RNAi therapeutics.

Targeted RNAi Molecule (TRiMTM) Platform

Arrowhead’s Targeted RNAi Molecule, or TRiMTM, platform utilizes ligand-mediated delivery and is designed to enable tissue-specific targeting while being structurally simple. Targeting has been core to Arrowhead’s development philosophy and the TRiMTM platform builds on more than a decade of work on actively targeted drug delivery vehicles. Arrowhead scientists have discovered ways to progressively “TRiM” away extraneous features and chemistries and retain optimal pharmacologic activity.

The TRiMTM platform comprises a highly potent RNA trigger with the following components optimized, as needed, for each drug candidate: a high affinity targeting ligand; various linker and chemistries; structures that enhance pharmacokinetics; and highly potent RNAi triggers with sequence specific stabilization chemistries.

Therapeutics developed with the TRiMTM platform offer several advantages: simplified manufacturing and reduced costs; multiple routes of administration; potential for improved safety because there are less metabolites from smaller molecules, thereby reducing the risk of intracellular buildup.

At Arrowhead, we also believe that for RNAi to reach its true potential, it must target organs outside the liver. Arrowhead is leading this expansion with the TRiMTM platform that holds the promise of reaching multiple tissues, including liver, lung, and tumor.

RNA Chemistries

The structure and chemistries of the oligonucleotide molecules used to trigger the RNAi mechanism can be tailored for optimal activity. Arrowhead’s broad portfolio of RNA trigger structures and chemistries, including some proprietary structures, enable the company to optimize each drug candidate on a target-by-target basis and utilize the combination of structure and chemical modifications that yield the most potent RNAi trigger.

As a component of the TRiM platform, Arrowhead’s design philosophy on RNA chemical modifications is to start with a structurally simple molecule and only add selective modification and stabilization chemistries as necessary to achieve the desired level of target knockdown and duration of effect. The conceptual framework for the stabilization strategy starts with a more sophisticated RNAi trigger screening and selection process that identifies potent sequences rapidly in locations that others may miss. We pursue chemical stabilization strategies with a target duration of effect of 30-90 days, and typically limit the use of strategies that produce longer activity because we anticipate that such strategies will increase long-term safety risks.

Intellectual Property

Our intellectual property portfolio provides broad freedom to apply multiple RNAi delivery technologies, chemistries, structures and manufacturing techniques in the development of novel therapeutics. Access to a broad range of technologies allows us to choose the best approach for a wide range of gene targets and disease indications.